Anti-RIPK2 monoclonal antibody

X-chromosome-linked inhibitor of apoptosis protein (XIAP) controls cell survival in several regulated cell death pathways and coordinates a range of inflammatory signaling events. Initially identified as a caspase-binding protein, it was considered to be primarily involved in blocking apoptosis from both intrinsic as well as extrinsic triggers. However, XIAP also prevents TNF-mediated, receptor-interacting protein 3 (RIPK3)-dependent cell death, by controlling RIPK1 ubiquitylation and preventing inflammatory cell death. The identification of patients with germline mutations in XIAP (termed XLP-2 syndrome) pointed toward its role in inflammatory signaling. Indeed, XIAP also mediates nucleotide-binding oligomerization domain-containing 2 (NOD2) proinflammatory signaling by promoting RIPK2 ubiquitination within the NOD2 signaling complex leading to NF-kappa B and MAPK activation and production of inflammatory cytokines and chemokines. Overall, XIAP is a critical regulator of multiple cell death and inflammatory pathways making it an attractive drug target in tumors and inflammatory diseases.

An association has long been suspected between febrile seizures and interleukin-1 beta, the most potent endogenous pyrogen. Interleukin-1 beta production increases after double-stranded RNA stimulation in leukocytes of febrile seizure patients. To elucidate the genetics of the immune response, the gene expression pattern after double-stranded RNA stimulation was investigated using DNA microarray. Compared with the control group, expression of the genes ACCN4 (sodium channel), KCNC3 (potassium channel), GABRE (gamma-aminobutyric acid receptor epsilon subunit), RIPK2 (receptor interacting protein kinase-2), TLR4 (toll-like receptor-4), IL26 (interleukin-26), and TNF (tumor necrosis factor), and CASP1 (caspase-1) was increased in the febrile seizure group (P < 0.01). Because RIPK2 and CASP1 are associated with interleukin-1 beta production, increased expression might cause increased interleukin-1 beta production in the febrile seizure patients. The induced expression of several ion channel genes by double-stranded RNA may affect neuronal excitability which leads to seizure susceptibility during infection. (C) 2009 by Elsevier Inc. All rights reserved.